RNF213 governs divergent tumor-immune dynamics across human cancers: a prognostic biomarker for immunotherapy stratification.

Purpose: RNF213 encodes one of the largest E3 ubiquitin ligases in the human proteome, playing essential roles in ubiquitination, DNA damage repair, and immune system regulation. Although RNF213 has been extensively studied in Moyamoya disease, its involvement in cancer biology remains insufficiently understood. This study seeks to conduct a comprehensive pan-cancer analysis to explore RNF213 expression, mutation characteristics, its correlation with clinical outcomes, and its potential as a prognostic biomarker and a therapeutic target, particularly in the context of immunotherapy.

Methods: Leveraging data from The Cancer Genome Atlas (TCGA) and additional publicly available datasets, we performed a systematic analysis of RNF213 expression patterns, mutation frequencies, and their relationships with clinical outcomes. We also conducted survival analyses to assess the impact of RNF213 expression on the efficacy of immune checkpoint blockade therapies.

Results: RNF213 demonstrated variable expression levels across different cancer types, with notable overexpression observed in glioblastoma and endometrial carcinoma, while underexpression was detected in lung adenocarcinoma and prostate adenocarcinoma. Elevated RNF213 expression was linked to unfavorable survival outcomes in acute myeloid leukemia and low-grade glioma, whereas it was associated with better survival in sarcoma and skin cutaneous melanoma. RNF213 expression showed a positive association with immune-related genes and immune cell infiltration, particularly in glioblastoma and breast cancer. Furthermore, patients with high RNF213 expression experienced significant survival advantages when receiving combined anti-PD-1 and anti-CTLA-4 immunotherapies.

Conclusion: This study highlights RNF213's dual functionality in tumor progression and immune modulation, underscoring its potential as both a prognostic biomarker and a therapeutic target. The findings suggest that RNF213 may play a pivotal role in determining immunotherapy outcomes, warranting further exploration into its underlying mechanisms and clinical applications.